Microglial heparan sulfate in the modulation of APOE function and neurodegeneration

小胶质细胞硫酸乙酰肝素调节 APOE 功能和神经退行性变

• 批准号: 10555329
• 负责人: YU YAMAGUCHI
• 金额: $ 58.1万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555329
• 关键词: ATP binding cassette transporter 1; Ablation; Affinity; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid deposition; Animals; Apolipoprotein E; Attention; Behavioral; Binding; Binding Proteins; Brain; Brain Pathology; Cell surface; Charge; Cholesterol; Code; Core Protein; Data; Dementia; Development; Excision; Exhibits; Extracellular Matrix; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genomics; Goals; Heparan Sulfate Proteoglycan; Heparin; Heparitin Sulfate; Heparitin sulfotransferase; Human; Human Genetics; Immunomodulators; Impaired cognition; In Vitro; Late Onset Alzheimer Disease; Ligands; Link; Lipids; Maintenance; Mediating; Medical; Microglia; Molecular; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurons; Pathway interactions; Phenotype; Play; Polysaccharides; Process; Protein Isoforms; Proteins; Recurrent disease; Regulation; Relative Risks; Reporting; Research; Research Priority; Resistance; Risk; Risk Factors; Role; Senile Plaques; Series; Signal Transduction; Sulfate; Surface; Synapses; TREM2 gene; Variant; Woman; apolipoprotein E-3; apolipoprotein E-4; cationic antimicrobial protein CAP 37; cholesterol transporters; experimental study; functional genomics; genetic association; genetic risk factor; genomic data; glial activation; glycosylation; immunoregulation; in vivo; insight; mouse model; neuroinflammation; novel; presenilin-1; receptor; response; sugar; tau Proteins; therapeutic target

Heparan sulfate (HS), a sulfated glycan expressed at the cell surface and in extracellular matrix, has long attracted attention as a putative factor involved in Alzheimer's disease (AD), based on circumstantial evidence from in vitro and clinicopathological studies. Nevertheless, the functional significance of HS in AD, especially in the late-onset type (LOAD) that comprises more than 90% of AD cases, is elusive. Recent human genomic studies implicate ApoE and microglia as dominant contributors to neurodegeneration in LOAD. The APOE gene is the strongest known genetic risk factor for LOAD. Accumulating data indicate that ApoE proteins exert immunomodulatory effects on microglia, and that this function of ApoE is at least partly mediated by the TREM2 receptor, another AD risk factor that is expressed by microglia. Among the three human APOE alleles, the APOE4 allele confers an increased risk for LOAD, while the APOE2 allele confers a decreased risk relative to the more common APOE3 allele. The molecular basis of these allele- specific risk variations is one of the key unanswered issues in AD research. In this context, it is interesting to note that ApoE proteins bind HS in an isoform-specific manner — ApoE4 exhibits 2- to 3-fold greater affinity for HS than ApoE2 and ApoE3, thus apparently correlating with their relative AD risks. Furthermore, a recent report regarding the unique case of a Columbian woman, who carries a highly detrimental PSEN1E280A mutation, suggests that her APOE3 "Christchurch" mutation, which abolishes the affinity of ApoE3 for HS, confers strong protection against neurodegeneration and cognitive impairment. Also suggesting the functional involvement of HS in LOAD are recurrent reports of genetic association of HS sulfotransferase genes with LOAD. In a series of preliminary studies, we have obtained multiple pieces of evidence suggesting that the strong interaction of HS with ApoE4, relative to its interactions with ApoE2 and ApoE3, is the key underlying mechanism by which ApoE4 exerts a detrimental effect on the brain. Significantly, we have found that haploinsufficient reduction in HS expression leads to the mitigation of synapse loss and microglial activation in the PS19 TauP310S mouse model. We hypothesize that HS plays a critical role in mediating the ApoE4 effect on microglial response and function, and that the detrimental effect of the APOE4 allele is mainly due to its stronger interaction with the 3-O sulfate-rich HS species expressed in microglia. We will: (1) determine the role of HS in ApoE-TREM2 interaction and signaling in microglia; (2) determine the role of microglial HS in ApoE/ABCA1-mediated cholesterol efflux; and (3) examine in vivo effects of microglial HS on brain pathology and function in AD mouse models. This research will provide entirely novel insights into the role of HS in microglia, and moreover, into long-term questions regarding the isoform-specific risk of APOE variants. Successful completion of this project will reveal the ApoE4-HS interaction as a promising therapeutic target for reducing AD risk in APOE4 carriers.

硫酸肝素（HS）是一种在细胞表面和细胞外基质中表达的硫酸化聚糖，具有很长的 基于间接 体外和临床病理学研究的证据。然而，HS在 AD，尤其是在超过90％的AD病例的后期发作类型（负载）中，这是难以捉摸的。最近的 人类基因组研究将APOE和小胶质细胞视为神经退行性的主要因素 加载。 APOE基因是负载的强烈遗传风险因素。累积指示数据 APOE蛋白对小胶质细胞执行免疫调节作用，并且APOE的这种功能至少是 部分由TREM2受体介导，这是由小胶质细胞表达的另一种AD风险因素。在 三个人类APOE等位基因，APOE4等位基因承认负载的风险增加，而APOE2等位基因 相对于更常见的APOE3等位基因，风险下降。这些等位基因的分子基础 - 特定的风险差异是广告研究中的关键未解决问题之一。在这种情况下，它很感兴趣 要注意，ApoE蛋白以同工型特异性方式结合HS- APOE4表现出2至3倍 对HS的亲和力比APOE2和APOE3，因此显然与它们的相对AD风险相关。此外， 关于哥伦比亚妇女的独特案例的最新报告 PSEN1E280A突变，表明她的APOE3“ Christchurch”突变，它废除了亲和力 HS的APOE3为神经变性和认知障碍提供了强烈的保护。还 提示HS在负载中的功能参与是HS遗传关联的复发报告 具有负载的硫代转移酶基因。在一系列初步研究中，我们获得了多个部分 证据表明HS与APOE4的强烈相互作用相对于其与APOE2的相互作用 APOE3是APOE4对大脑产生不利影响的关键基础机制。 值得注意的是，我们发现HS表达的单倍降低会导致缓解 PS19 TAUP310S小鼠模型中的突触损失和小胶质细胞激活。我们假设HS播放 在介导APOE4对小胶质响应和功能的影响方面的关键作用，并确定 APOE4等位基因的影响主要是由于其与3-O富含硫酸盐的HS物种的相互作用更强 在小胶质细胞中表达。我们将：（1）确定HS在APOE-Trem2相互作用中的作用和信号传导 小胶质细胞； （2）确定小胶质细胞HS在APOE/ABCA1介导的胆固醇外排的作用； （3） 检查小胶质细胞HS对AD小鼠模型中脑病理学和功能的体内影响。这 研究将为HS在小胶质细胞中的作用以及长期提供完全新颖的见解 有关APOE变体的同工型特异性风险的问题。成功完成该项目将 揭示APOE4-HS相互作用是降低APOE4载体AD风险的有希望的治疗靶标。